ACID BASE PATHOPHYSIOLOGY AND DISEASE STATES
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Transcript of ACID BASE PATHOPHYSIOLOGY AND DISEASE STATES
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ACID BASE PATHOPHYSIOLOGY
AND DISEASE STATES
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The Four Cardinal Acid Base Disorders
M acidosis
M alkalosis
R acidosis
R alkalosis
Disorder pH pCO2 [HCO3-]
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Metabolic Acidosis: The “Anion Gap”
Na+
Cl-
HCO3-
Alb-
[Na+] - ([Cl-] + [HCO3-])
~ 10-12 mM/L
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Na+ + Cl- + H+ + HCO3-
Na+ + Cl- + H2CO3
Na+ + Cl- + CO2 + H2O
What happens after HCl addition:
Na+ + Cl-
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Metabolic Acidosis: The “Anion Gap”
Na+
Cl-
HCO3-
Alb-
[Na+] - ([Cl-] + [HCO3-])
Na+
Cl-
HCO3-
Alb-
Nl Anion gapM acidosis
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Na+ + A- + Cl- + H+ + HCO3-
Na+ + A- + Cl- + H2CO3
Na+ + A- + Cl- + CO2 + H2O
What happens after AH additionwhere “A” is a retained anion:
Na+ + A- + Cl-
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Metabolic Acidosis: The “Anion Gap”
Na+
Cl-
HCO3-
Alb-
Na+
Cl-
HCO3-
Alb-
[Na+] - ([Cl-] + [HCO3-])
Nl Anion gapM acidosis
Na+
Cl-
HCO3-
Alb-
A-
High Anion gapM acidosis
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Clinician short-hand you should know:
Na+ Cl- BUN K+ HCO3
- creatinine Glucose
140 105 30 4.5 25 1.5
90
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140 105 30 Glucose 904.5 25 1.5
141 105 27 Glucose 1004.2 6 1.2
139 113 33 Glucose 1263.7 16 1.4
And now, it’s time for: “Calculate That Gap”
140 -(105 + 25) = 10 = normal
141 - (105 + 6) = 30 = high
139 - (113 + 16) = 10 = normal
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Differential Dx of high-anion gap acidosis: "SLUMPED":
SalicylatesLactic acidosisUremiaMethanol intoxicationPaint sniffing (toluene)Ethylene glycol intoxication
DKA or alcoholic ketoacidosis
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Usually: mixed respiratory alkalosis & metabolic acidosis (rare: metab pure acidosis)
Toxic at < 5 mEq/l, so no anionic contrib to AG No increase in osmolal gap ([ASA] < 5 mM)
Salicylates - ± Hx aspirin ingestion, nausea, tinnitus, unexplained hyperventilation, noncardiogenic pulmonary edema, elevated prothrombin time
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Treatment for salicylate intoxication:
Un-ionized form (protonated) enters the brain and is excreted poorly
So….alkalinize (HCO3 infusion) to maximize renal excretion (dialysis)
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Lactic acidosis -
Type A = increased O2 demand or decreased O2 delivery
Type B = Malignancies (lymphoma)Phenformin, metforminhepatic failureacute respiratory alkalosis (salicylates)HAARTcongenital (glycogen storage disease type I)etc
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Uremia is indicated by BUN, creatinine(chronicity by kidney size and Hct).
Methanol - presents with ± abdominal pain, vomiting, headache; CT: BL putamen infarctsvisual disturbance (optic neuritis)
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Normal retina (left); optic neuritis (right)
Methanol intoxication: neurological effects
Putameninfarcts
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Anion gap may be > 50 Osmolal gap > 10 mOsm
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No increase in osmolal gap
Paint sniffing (“huffing”)(toluene) may present as eitheranion gap acidosis or normal gap acidosisAnion = hippurate
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Ethylene glycol - presents with ± CNS disturbances, cardiovascular collapse, respiratory failure, renal failure
Oxalate crystals (octahedral or dumbell) in urine are diagnostic
Anion gap may be > 50
Osmolal gap > 10 mOsm
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“The rotund rodents chew through brake lines and radiator hoses in search of a fix of ethylene glycol…”“Marmots have an amazing ability to handle toxic substances. To tranquilize them, they need the same dose as a bear, and a bear will be down for 40 minutes while a marmot will be back up in 5. If you have to redrug them, it’s really hard to make them unconscious again.”
National WildlifeFeb/Mar, 2002
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Oxalate crystals
“back of the envelope”
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1. Ethanol infusion to compete with alcohol dehydrogenase (dialysis)
OR
2. “Antizol” (fomepizole) (inhibits ADH)load, then 10 mg/kg q12 x 4
Treatment for methanol & ethylene glycol intoxication:
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Diabetic ketoacidosis -
Key clinical features are:
type I DM (i.e. no insulin)
a trigger: e.g. sepsis, fracture, stroke
hyperglycemia
ECF vol depletion & renal insufficiency
acetoacetic- and hydroxybutyric- acids
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Alcoholic ketoacidosis - key clinical features are recent stopping ingestion of ethanol, hypoglycemia, and contracted ECF (usually due to vomiting)
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THE SERUM OSMOLALITY CAN HELP WITH THE DIAGNOSISIN HIGH ANION GAP ACIDOSES
Step 1: Calculate Osm = 2[Na+] + glucose/18 + BUN/2.8
Step 2: Measure Osm (freezing point depression)
3. Osmolal gap (measured - calc) should be ≤ 10
Osm gap due to small, osmotically-active molecules:
mannitol (no acidosis)ethanol (acidosis = AKA)isopropanol (a "drunk" with ketones,
but no acidosis)methanol (acidosis)ethylene glycol (acidosis)
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Does metabolic acidosis causehyperkalemia via H+/K+ exchange?
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Na+ + Lact- + Cl- + H+ + HCO3-
Na+ + Lact- + Cl- + H2CO3
Lact- HCO3-
Na+ + Cl- + HCO3- (normal HCO3
-,normal gap)
Acute lactic acidosis from seizures(“closed” system”; lactate reabsorbed)
Na+ + Lact- + Cl- (low HCO3-,high gap)
Na+ + Lact- + Cl- + CO2 + H2O
Na+ + Cl- + HCO3-
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Time (minutes)
Acute lactic acidosis from seizures(“closed” system”; lactate reabsorbed)
Seizure
[K+]
[HCO3-]
pH
A. Gap
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Principles of K+/H+ Exchange:
1. Occurs if anion is impermeable 2. Limited if anion is permeable (“organic”)
K+
H+
Cl-H+
A-
K+
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1. GI bicarbonate loss:diarrheavillous adenomapancreatic, biliary, small bowel fistulaeuretero-sigmoidostomyobstructed uretero-ileostomy
Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)
metabolic acidosis
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Pancreas
Ileum
Colon
Pancreas
Ileum
Colon
Diarrhea Causes Loss of HCO3-
And a Normal Anion Gap AcidosisAnd Hypokalemia
HCO3-
HCO3-
Cl-
HCO3-
Cl-
K+ HCO3-
Normal Diarrhea
Cl-
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Flooding the colon or CCD with HCO3
- instead of Cl- drives K+ secretion
Na+Na+
K+ K+
Cl-
HCO3-
K+
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Pancreas
Ileum
Pancreatic fistula or transplant:loss of HCO3
-
Skin orurinary bladder
HCO3-
Cl-
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Ileal loop
Obstructed Uretero-ileostomy Causes a Normal Anion Gap Acidosis
Obstructedileal loop
HCO3-Ureter Skin
Cl-
Ileostomy bag
Cl-
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The underlying assumption is that NH4+
is excreted and maintains electroneutrality: ([Na+] + [K+] + [NH4
+]) - [Cl-] = 0
Since NH4+ is unmeasured,
a negative urine anion gap indicates NH4
+Cl excretion(i.e. normal renal tubule acidification)
How to differentiate GI HCO3- loss
from renal HCO3- loss?
Use the urinary anion gap
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A positive urine anion gap ~ no NH4+Cl excretion
(i.e. low renal tubule acidification)
Normal acidotic: closed circlesDiarrhea: closed triangles
Type 1 or IV RTA: open circles
Battle et al, NEJM 1988
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2. Ingestions & infusionsammonium chloridehyperalimentation (arginine/lysine-rich)
3. Renal bicarbonate (or equivalent) lossproximal RTAdistal RTAtype IV RTAearly renal failureacetazolamidehydrated DKA
Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)
metabolic acidosis
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Proximal RTA (“Type II”)
HCO3- (1) Na+
(3) HCO3-H+
CO2 H2O+
H+
Na+
Na+
HCO3-
glucoseamino acidsuratephosphate
DefectiveNa+ - dependentresorption =Fanconi’sSyndrome
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Inheritance Gene Geneproduct
Clinicalfeatures
Genetically-Defined Proximal RTAs
Autosomalrecessive
SLC4A4 NBC1 Prox RTAcorneal Ca++
pancreatitis
Autosomalrecessive
CA2 CarbonicAnhydraseII
ProximalOrdistalOr“hybrid” RTA;osteopetrosis;cerebral Ca++
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HCO3- in
moles/time
filtered
GFR x [HCO3-]plasma = “filtered load of HCO3
-”
HCO3- Tm
UHCO3V
Type II Renal Tubular Acidosis (“Proximal RTA”)
NewHCO3
Tm
UHCO3V
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Type II Renal Tubular Acidosis (“RTA”)
HCO3-
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Net acid excretion =urinary NH4
+
+urinary “titratable acid” (H2PO4
-)-
urinary HCO3-
H+
NH4+
NH3+
HCO3-
+
H2CO3
HPO4-- +H2PO4
-
Not titratable;need to measure
Present inProx RTA
Titratableacid
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Flooding ofCCD with
HCO3- exceeds
its resorptive capacity;
HCO3- becomes
“a poorly resorbed anion”
Na+
K+
Na+
K+
Principal cell
a IC cell
IC cell
HCO3-
Cl-
HCO3-
Cl-
Cl-
H+ATP
ADP + Pi
H+ATP
ADP + Pi
Cl-
pHmin = 5
HCO3-
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Glomerulus
Proxtubule
CCD
How Diarrhea and Proximal RTA Are Alike
Pancreas
Ileum
ColonK+ HCO3
-
HCO3-
HCO3-
K+ HCO3-
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Urine pH in proximal RTA
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Fractional excretionof HCO3
- in proximal RTA
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Diminished proximal resorption of HCO3-
Plasma [HCO3-] 10-15 mEq/L
Urine pH depends on plasma [HCO3-] & GFR
relative to proximal HCO3- Tm
Fractional HCO3- excretion high (15-20%)
at nl plasma [HCO3-]
Plasma [K+] reduced, worsens with HCO3- therapy
Dose of daily HCO3- required: 10-15 mEq/kg/d
Non-renal: rickets or osteomalacia
Features of Proximal Renal Tubular Acidosis (“Type II”)
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3. Renal bicarbonate (or equivalent) lossproximal RTAdistal RTAtype IV RTAearly renal failureacetazolamidehydrated DKA
Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)
metabolic acidosis
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Distal RTA
Na+
K+
Na+
K+
Principal cell
a IC cell
IC cell
HCO3-
Cl-
HCO3-
Cl-
Cl-
H+ATP
ADP + Pi
H+ATP
ADP + Pi
Cl-
Aldosterone
amphotericin
Auto-immune
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Hypo-kalemia
indistal RTA:
H + nolonger shunts
Na +
current soK+ must
do so
Na+
K+
Na+
K+
Principal cell
a IC cell
IC cell
HCO3-
Cl-
HCO3-
Cl-
Cl-
H+ATP
ADP + Pi
H+ATP
ADP + Pi
Cl-
Aldosterone
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Urine pH in distal RTA
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Fractional excretionof HCO3
- in distal RTA
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Diminished distal H+ secretion (autoimmune)or backleak of secreted H+ (ampho-B)
Plasma [HCO3-] may be below 10 mEq/L
Urine pH always > 5.5
Fractional HCO3- <3% at nl plasma [HCO3
-]
Plasma [K+] reduced
Dose of daily HCO3- required: 1-2 mEq/kg/d
Non-renal: nephrocalcinosis, renal stones
Features of Classic Distal Renal Tubular Acidosis (“Type I”)
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Inheritance Gene Geneproduct
Clinicalfeatures
Genetically-Defined Type I Distal RTAs-1
Autosomalrecessive
SLC4A1 AE1 (G710D)V850)
Acute illnessor growthfailure inchildhood± deafness
Autosomaldominant
SLC4A1 AE1(A858DR589SR589H)
Milder;Hearing is OK
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Inheritance Gene Geneproduct
Clinicalfeatures
Genetically-Defined Type I Distal RTAs-2
Autosomalrecessive
ATP61 58 kDasubunit:vacuolarH+ATPase
Distal RTA;sensori-neural hearingloss
Autosomalrecessive
ATP6N1B 116 kDasubunit:vacuolarH+ATPase
Distal RTA;no hearingloss
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3. Renal bicarbonate (or equivalent) lossproximal RTAdistal RTAtype IV RTAearly renal failureacetazolamidehydrated DKA
Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)
metabolic acidosis
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Hyporenin-hypo
aldosteronism
Na+
K+
Na+
K+
Principal cell
a IC cell
IC cell
HCO3-
Cl-
HCO3-
Cl-
Cl-
H+ATP
ADP + Pi
H+ATP
ADP + Pi
Cl-
Aldosterone
Diabetesis the maincause
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Urine pH generally < 5.5as if the H+ gradient is OK but the H+ “throughput” is poor
Plasma [HCO3-] usually above 15 mEq/L
Major problem: hyperkalemiasuppresses ammoniagenesis
Hypoaldosteronism(“Type IV RTA”)
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Total Body K+ Excess Decreases Proximal Tubule Acidification and Ammoniagenesis
via Intracellular Alkalosis
2. Total body K+ excess
K+
3. K+ entryinto proximal tubule cells
HCO3- (1) Na+
(3) HCO3-H+
CO2 H2O+
H+
Na+
H+
4. Alkalinization of prox tubule cellby K+/H+ exchange
1. Failed CCD K+ secretion
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“Voltage” typeHyperkalemicDistal RTA
Na+
K+
Na+
K+
Principal cell
a IC cell
IC cell
HCO3-
Cl-
HCO3-
Cl-
Cl-
H+ATP
ADP + Pi
H+ATP
ADP + Pi
Cl-
Aldosterone
ObstructionSickle CellAmilorideTrimethoprimPentamidine“PHA”
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Urine pHLasix +
amiloride
Lasix
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Urine pH generally > 5.5as if the H+ gradient is poor AND the H+ “throughput” is poor
Plasma [HCO3-] usually above 15 mEq/L
Again: hyperkalemiasuppresses ammoniagenesis
“Voltage type” Hyperkalemic Distal RTA
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Inheritance Gene Geneproduct
Clinicalfeatures
Genetically-Defined Hyperkalemic Distal RTAs-1
Autosomaldominant
MLR Mineralo-corticoidreceptor
PHA* I:Hyperkalemicdistal RTA
* “PHA” = Pseudohypoaldosteronism
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Inheritance Gene Geneproduct
Clinicalfeatures
Genetically-Defined Hyperkalemic Distal RTAs-1
Autosomalrecessive
SNCC1A aENaC PHA I
Autosomalrecessive
SNCC1B ENaC PHA I
Autosomalrecessive
SNCC1G ENaC PHA I
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Aldosterone deficiency or resistance (“voltage”)
Plasma [HCO3-] usually above 15 mEq/L
Urine pH depends:generally < 5.5 in hypoaldosteronismgenerally > 5.5 in voltage defect
Fractional HCO3- excretion <3% at nl
plasma [HCO3-]
Plasma [K+] elevated
Dose of daily HCO3- required: 1-3 mEq/kg/d
Non-renal: none
Features of the Hyperkalemic Distal RTAs
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Normal Gap Acidosis With Nl Creatinine
Urinary anion gapNegative
(high NH4+)
GI HCO3- loss
Proximal RTAacetazolamide
Positive(low NH4
+)
Urine pH& plasma [K+]
Urine pH < 5.5 & high[K+]
Hypo-aldosteronismRTA(type IV)
Urine pH > 5.5 & low/nl[K+]
Distal RTA(“Type I”):secretory or
gradient defect
VoltageDefect
Urine pH > 5.5 & high[K+]
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2. Ingestions & infusionsammonium chloridehyperalimentation (arginine/lysine-rich)
3. Renal bicarbonate (or equivalent) lossproximal RTAdistal RTAtype IV RTAearly renal failureacetazolamidehydrated DKA
Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)
metabolic acidosis
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Excretion of the Daily Acid Load is Decreased inChronic Renal Failure (CRF) or
Distal Renal Tubular Acidosis (dRTA)
Kim et al, AJKD 1996
Chronic Renal Failure dRTA Acid-loaded controls
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2. Ingestions & infusionsammonium chloridehyperalimentation (arginine/lysine-rich)
3. Renal bicarbonate (or equivalent) lossproximal RTAdistal RTAtype IV RTAearly renal failureacetazolamidehydrated DKA
Causes of a “normal anion gap”(A.K.A. “hyperchloremic”)
metabolic acidosis
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Renal handling of acetoacetatein the dog
Schwab and Lotspeich 1954
Self-inhibitionof absorption
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Renal handling of acetoacetateAnd -OH butyrate in the rat
Ferrier et al, 1992
Endogenous levels:Good resorption
Elevated levels:Poor resorption
Self-inhibitionof absorption
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Na+ + AcAc- + Cl- + H+ + HCO3-
Na+ + AcAc- + Cl- + H2CO3
Na+ + AcAc- + Cl- + CO2 + H2O
Na+ + Cl-
Renal loss of filtered AcAc-
Pathophysiology of normal anion gap acidosisin diabetic ketoacidosis
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Dumping of keto-anions with hydration in DKA
Adrogué 1984
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DKAs admitted hydrated have non-anion gap acidosis
Adrogué 1984
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The Four Cardinal Acid Base Disorders
M acidosis
M alkalosis
R acidosis
R alkalosis
Disorder pH pCO2 [HCO3-]
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Vomiting
H+ loss
Plasma pHand HCO3
Distal K+
secretionK+ depletion
High HCO3 Tm
NH3/NH4+
secretion
CCD HCO3
resorption
Renal HCO3
resorption
H+/K +
ATPase
pCO2
K+ loss, K + intake
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Vomiting
High HCO3 Tm
CCD HCO3
resorption
Renal HCO3
resorption
H+ loss
Plasma pHand HCO3
Distal K+
secretionK+ depletion
NH3/NH4+
secretion
H+/K +
ATPase
pCO2
K+ loss, K + intake
Na+ loss
ECFvolume
Sympathetic tone
GFR
GFR x PHCO3
Renin
Local Ang II
Systemic Ang II
Aldosterone
Low filtered HCO3 load
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Na+ loss
ECFvolume
Sympathetic tone
GFR
GFR x PHCO3
Renin
Local Ang II
Systemic Ang II
Aldosterone
Vomiting
High HCO3 Tm
CCD HCO3
resorption
Renal HCO3
resorption
H+ loss
Plasma pHand HCO3
Distal K+
secretionK+ depletion
NH3/NH4+
secretion
H+/K +
ATPase
pCO2
K+ loss, K + intake
Low filtered HCO3 load
Chloride loss TGfeedback
Distalchloridedelivery
CCD HCO3
Secretion( IC cell)
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Na+ loss
ECFvolume
Sympathetic tone
GFR
Filtered HCO3
Renin
Local Ang II
Systemic Ang II
Vomiting
High HCO3 Tm
CCD HCO3
resorption
Renal HCO3
resorption
H+ loss
Plasma pHand HCO3
Distal K+
secretionK+ depletion
NH3/NH4+
secretion
H+/K +
ATPase
pCO2
K+ loss, K + intake
Low filtered HCO3 load
Chloride loss TGfeedback
Distalchloridedelivery
CCD HCO3
secretionAldosterone
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DIFFERENTIAL DIAGNOSIS OF METABOLIC ALKALOSIS USING URINE Cl
Normal Urine [Cl-]
MineralocorticoidismRAS, aldosteronism11-DH deficienciesBartter’s
Diuretics (early)
Severe K+ depletion
Diuretics (late)
Low Urine [Cl-]
VomitingNG suction
Posthypercapnia
Low Cl- intake
Cystic fibrosis
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The Four Cardinal Acid Base Disorders
M acidosis
M alkalosis
R acidosis
R alkalosis
Disorder pH pCO2 [HCO3-]
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Minuteventilation
pCO2 pO2
Centralchemoreceptorsventilation
Carotid &aortic bodies
20 40 60 4080120
The Drives to Ventilation: CO2 and O2
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Causes of Respiratory Acidosis
Chronic
10 mm Hg pCO2 3.5 mEq/L HCO3
-
Acute
10 mm Hg pCO2 1 mEq/L HCO3
-
Asthma
Pulmonary edema
Cardiac arrest
Drug overdose
Sleep apnea
Chronic ObstructivePulmonary Disease(COPD)
Neuromuscular (e.g.Lou-Gehrig’s)
Obesity/Pickwickian
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NH4+NH4
+
Na+
Chronically Elevated pCO2 StimulatesFormation of New HCO3
- by Ammoniagenesis
H+H+
Na+
NH3NH3NH4
+
HCO3-
Glutamine NH3 + CO2 + H2O
Glutaminase
Proximal tubule
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204060pCO2 isobars
HCO3-
pH
25
7.40
Acute vs Chronic Respiratory Acidosis
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The Four Cardinal Acid Base Disorders
M acidosis
M alkalosis
R acidosis
R alkalosis
Disorder pH pCO2 [HCO3-]
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Causes of Respiratory Alkalosis
Chronic
10 mm Hg pCO2 3-5 mEq/L HCO3
-
Acute
10 mm Hg pCO2 2 mEq/L HCO3
-
Fear
Pain
Acid-base exams…
Anxiety
Altitude; Psychosis
Sepsis; Stiff lungs
Liver failure
Salicylates
Pregnancy
Neurological
Iatrogenic (wrongventilator setting)
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HCO3- in
moles/time
filtered
GFR x [HCO3-]plasma = “filtered load of HCO3
-”
HCO3- Tm
UHCO3V
Chronic Reduction in pCO2 Lowers HCO3- Tm
NewHCO3
Tm
UHCO3V
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145 95 303.5 25 1.8
RA-ABG: 7.50 /pCO2 33 /pO2 105
EXTRA CREDIT:WHAT IS THE ACID-BASE DISTURBANCE?
3. But the pCO2 is too low for a normal HCO3-
= respiratory alkalosis
This is the “Triple Ripple”
1. Anion gap is high (20) = addition oforganic acid (“footprints”)
2. pH is high = alkalosismust be superimposed on Anion Gap acidosisbut respiratory alkalosis would lower HCO3
-
so must be metabolic alkalosis (vomiting?)
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End of Patho-Physiology Section(Acid-Base Part 2)
OR
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NH4+
NH4+ undergoes counter-current
multiplication-1
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Descending limb
Ascending limb
Counter-Current Multiplication
1. At the start: all cups have 10 pennies;2. All new incoming cups have 10 pennies
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